Thiazole compounds useful as inhibitors of protein kinase

ABSTRACT

The present invention provides a compound of formula I:  
                 
or a pharmaceutically acceptable derivative thereof. These compounds are inhibitors of protein kinases, particularly inhibitors of GSK3, Aurora2, and Syk mammalian protein kinases. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of utilizing those compounds and compositions in the treatment of various protein kinase mediated disorders.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. Provisional Patent Application60/295,158 filed Jun. 1, 2001, the contents of which are incorporatedherein by reference.

FIELD OF THE INVENTION

The present invention relates to compounds that are protein kinaseinhibitors, pharmaceutically acceptable compositions comprising saidcompounds, and methods of use thereof. More particularly, the compoundsare inhibitors of GSK-3, Aurora2, and Syk protein kinases and are usefulfor treating, or lessening the severity of, a variety of diseases andconditions, such as diabetes, Alzheimer's disease, stroke, proliferativedisorders, and asthma.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recentyears by better understanding of the structure of enzymes and otherbiomolecules associated with target diseases. One important class ofenzymes that has been the subject of extensive study is the proteinkinases.

Protein kinases mediate intracellular signal transduction. They do thisby affecting a phosphoryl transfer from a nucleoside triphosphate to aprotein acceptor that is involved in a signaling pathway. There are anumber of kinases and pathways through which extracellular and otherstimuli cause a variety of cellular responses to occur inside the cell.Examples of such stimuli include environmental and chemical stresssignals (e.g. osmotic shock, heat shock, ultraviolet radiation,bacterial endotoxin, H₂O₂), cytokines (e.g. interleukin-1 (IL-1) andtumor necrosis factor a (TNF-α), and growth factors (e.g. granulocytemacrophage-colony-stimulating factor (GM-CSF), and fibroblast growthfactor (FGF). An extracellular stimulus may effect one or more cellularresponses related to cell growth, migration, differentiation, secretionof hormones, activation of transcription factors, muscle contraction,glucose metabolism, control of protein synthesis and regulation of cellcycle.

Many diseases and conditions are associated with abnormal cellularresponses triggered by protein kinase-mediated events. These diseasesinclude autoimmune diseases, inflammatory diseases, neurological andneurodegenerative diseases, cancer, cardiovascular diseases, allergiesand asthma, Alzheimer's disease or hormone-related diseases.Accordingly, there has been a substantial effort in medicinal chemistryto find protein kinase inhibitors that are effective as therapeuticagents.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinasecomprised of α and β isoforms that are each encoded by distinct genes[Coghlan et al., Chemistry & Biology, 7, 793-803 (2000); Kim and Kimmel,Curr. Opinion Genetics Dev., 10, 508-514 (2000)]. GSK-3 has beenimplicated in various diseases including diabetes, Alzheimer's disease,CNS disorders such as manic depressive disorder and neurodegenerativediseases, and cardiomyocete hypertrophy [WO 99/65897; WO 00/38675; andHaq et al., J. Cell Biol. (2000) 151, 117]. These diseases may be causedby, or result in, the abnormal operation of certain cell signalingpathways in which GSK-3 plays a role. GSK-3 has been found tophosphorylate and modulate the activity of a number of regulatoryproteins. These include glycogen synthase which is the rate limitingenzyme necessary for glycogen synthesis, the microtubule associatedprotein Tau, the gene transcription factor β-catenin, the translationinitiation factor e1F2B, as well as ATP citrate lyase, axin, heat shockfactor-1, c-Jun, c-Myc, c-Myb, CREB, and CEPBu. These diverse targetsimplicate GSK-3 in many aspects of cellular metabolism, proliferation,differentiation and development.

In a GSK-3 mediated pathway that is relevant for the treatment of typeII diabetes, insulin-induced signaling leads to cellular glucose uptakeand glycogen synthesis. Along this pathway, GSK-3 is a negativeregulator of the insulin-induced signal. Normally, the presence ofinsulin causes inhibition of GSK-3 mediated phosphorylation anddeactivation of glycogen synthase. The inhibition of GSK-3 leads toincreased glycogen synthesis and glucose uptake [Klein et al., PNAS, 93,8455-9 (1996); Cross et al., Biochem. J., 303, 21-26 (1994); Cohen,Biochem. Soc. Trans., 21, 555-567 (1993); Massillon et al., Biochem J.299, 123-128 (1994)]. However, in a diabetic patient where the insulinresponse is impaired, glycogen synthesis and glucose uptake fail toincrease despite the presence of relatively high blood levels ofinsulin. This leads to abnormally high blood levels of glucose withacute and long term effects that may ultimately result in cardiovasculardisease, renal failure and blindness. In such patients, the normalinsulin-induced inhibition of GSK-3 fails to occur. It has also beenreported that in patients with type II diabetes, GSK-3 is overexpressed[WO 00/38675]. Therapeutic inhibitors of GSK-3 are therefore potentiallyuseful for treating diabetic patients suffering from an impairedresponse to insulin.

GSK-3 activity has also been associated with Alzheimer's disease. Thisdisease is characterized by the well-known β-amyloid peptide and theformation of intracellular neurofibrillary tangles. The neurofibrillarytangles contain hyperphosphorylated Tau protein where Tau isphosphorylated on abnormal sites. GSK-3 has been shown to phosphorylatethese abnormal sites in cell and animal models. Furthermore, inhibitionof GSK-3 has been shown to prevent hyperphosphorylation of Tau in cells[Lovestone et al., Current Biology 4, 1077-86 (1994); Brownlees et al.,Neuroreport 8, 3251-55 (1997)]. Therefore, it is believed that GSK-3activity may promote generation of the neurofibrillary tangles and theprogression of Alzheimer's disease.

Another substrate of GSK-3 is β-catenin which is degradated afterphosphorylation by GSK-3. Reduced levels of β-catenin have been reportedin schizophrenic patients and have also been associated with otherdiseases related to increase in neuronal cell death [Zhong et al.,Nature, 395, 698-702 (1998); Takashima et al., PNAS, 90, 7789-93 (1993);Pei et al., J. Neuropathol. Exp, 56, 70-78 (1997)].

Aurora-2 is a serine/threonine protein kinase that has been implicatedin human cancer, such as colon, breast and other solid tumors. Thiskinase is involved in protein phosphorylation events that regulate thecell cycle. Specifically, Aurora-2 plays a role in controlling theaccurate segregation of chromosomes during mitosis. Misregulation of thecell cycle can lead to cellular proliferation and other abnormalities.In human colon cancer tissue, the aurora-2 protein has been found to beoverexpressed [Bischoff et al., EMBO J., 17, 3052-3065 (1998);Schumacher et al., J. Cell Biol., 143, 1635-1646 (1998); Kimura et al.,J. Biol. Chem., 272, 13766-13771 (1997)].

Syk is a tyrosine kinase that plays a critical role in FcεRI mediatedmast cell degranulation and eosiniphil activation. Accordingly, Sykkinase is implicated in various allergic disorders, in particularasthma.

It has been shown that Syk binds to the phosphorylated gamma chain ofthe FcεRI receptor via N-terminal SH2 domains and is essential fordownstream signaling [Taylor et al, Mol Cell Biol 1995; 15:4149].

Inhibition of eosinophil apoptosis has been proposed as key mechanismsfor the development of blood and tissue eosinophilia in asthma. IL-5 andGM-CSF are upregulated in asthma and are proposed to cause blood andtissue eosinophilia by inhibition of eosinophil apoptosis. Inhibition ofeosinophil apoptosis has been proposed as a key mechanism for thedevelopment of blood and tissue eosinophilia in asthma. It has beenreported that Syk kinase is required for the prevention of eosinophilapoptosis by cytokines (using antisense)[Yousefi et al, J Exp Med1996;183:1407].

The role of Syk in FcγR dependent and independent response in bonemarrow derived macrophages has been determined by using irradiated mousechimeras reconstituted with fetal liver cells from Syk −/− embryos. Sykdeficient macrophages were defective in phagocytosis induced by FcγR butshowed normal phagocytosis in response to complement [Kiefer et al, MolCell Biol 1998; 18:4209]. It has also been reported that aerosolized Sykantisense suppresses Syk expression and mediator release frommacrophages [Stenton et al, J Immunology 2000; 164: 3790].

Considering the lack of currently available treatment options for themajority of the conditions associated with protein kinases, especiallyGSK-3, Aurora-2, and Syk, there is still a great need for newtherapeutic agents that inhibit these protein targets.

SUMMARY OF THE INVENTION

The present invention addresses this need by providing a compound offormula I:

or a pharmaceutically acceptable derivative thereof, wherein R¹ and Ar¹are as defined below.

The present invention also provides a pharmaceutically acceptablecomposition comprising a compound of formula I.

The compounds and pharmaceutically acceptable compositions of thepresent invention are useful as inhibitors of GSK-3, Aurora-2, and Sykprotein kinases. Thus, they are also useful in methods for treating orlessening the severity of a variety of disorders, such as allergicdiseases, proliferative disorders, cancer, neurodegenerative disorders,and diabetes.

DESCRIPTION OF THE INVENTION

The present invention relates to a compound of formula I:

or a pharmaceutically acceptable derivative thereof, wherein:

-   -   R¹ is selected from R, halogen, CN, NO₂, or TR;    -   T is an optionally substituted C₁-C₄ alkylidene chain wherein up        to two methylene units of T are optionally and independently        replaced by O, N(R), C(O), S, SO, or SO₂;    -   each R is independently selected from hydrogen or an optionally        substituted CI-₆ aliphatic group, wherein:        -   two R bound to the same nitrogen atom are optionally taken            together with the nitrogen to form a 3-7 membered saturated,            partially unsaturated, or fully unsaturated ring having 0-2            heteroatoms, in addition to the nitrogen bound thereto,            independently selected from nitrogen, oxygen, or sulfur;    -   Ar¹ is an optionally substituted ring selected from:        -   (a) a 3-8 membered monocyclic or 8-10 membered bicyclic            saturated, partially unsaturated, or aryl ring;        -   (b) a 3-7 membered heterocyclic ring having 1-3 heteroatoms            independently selected from nitrogen, oxygen, or sulfur; or        -   (c) a 5-6 membered monocyclic or 8-10 membered bicyclic            heteroaryl ring having 1-4 heteroatoms independently            selected from nitrogen, oxygen, or sulfur, wherein:            -   Ar¹ is optionally substituted by one to four                substituents selected from the group consisting of:                -   (a) one group selected from QR, Ar², or QAr²; and                -   (b) up to four R2 groups;    -   each Q is indpendently selected from a valence bond or an        optionally substituted C₁₋₆ alkylidene chain, wherein:        -   one or two non-adjacent methylene units of Q are optionally            and independently replaced by —O—, —S—, —NR—, —C(O)—, —CO₂—,            —C(O)NR—, —OC(O)NR—, —C(O)C(O)—, —C(O)C(O)—, —NRC(O)—,            NRCO₂—, —NRC(O)NR—, —S(O)—, —SO₂—, —NRSO₂—, —SO₂NR—, or            —NRSO₂NR—;    -   each Ar² is an optionally substituted ring independently        selected from:        -   (a) a 3-8 membered monocyclic or 8-10 membered bicyclic            saturated, partially unsaturated, or aryl ring;        -   (b) a 3-7 membered heterocyclic ring having 1-3 heteroatoms            independently selected from nitrogen, oxygen, or sulfur; or        -   (c) a 5-6 membered monocyclic or 8-10 membered bicyclic            heteroaryl ring having 1-4 heteroatoms independently            selected from nitrogen, oxygen, or sulfur, wherein:            -   Ar² is optionally substituted by one to four R² groups;                and    -   each R² is independently selected from R, halogen, NO₂, CN, OR,        SR, N(R)₂, NRCOR, NRCON(R)₂, NRCO₂R, C(O)R, CO₂R, CON(R)₂,        OC(O)N(R)₂, SOR, SO₂R, SO₂N(R)₂, NRSO₂R, NRSO₂N(R)₂, C(O)C(O)R,        or C(O)CH₂C(O)R; wherein:        -   two R2 on adjacent positions on Ar¹ or Ar² are optionally            taken together to form a saturated, partially unsaturated,            or fully unsaturated 4-6 membered ring having 0-3            heteroatoms independently selected from nitrogen, oxygen, or            sulfur.

As used herein, the following definitions shall apply unless otherwiseindicated.

The phrase “optionally substituted” is used interchangeably with thephrase “substituted or unsubstituted.” Unless otherwise indicated, anoptionally substituted group may have a substituent at eachsubstitutable position of the group, and each substitution isindependent of the other.

The term “aliphatic” or “aliphatic group” as used herein means astraight-chain or branched C₁-C₈ hydrocarbon chain that is completelysaturated or that contains one or more units of unsaturation, or amonocyclic C₃-C₈ hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon that iscompletely saturated or that contains one or more units of unsaturation,but which is not aromatic (also referred to herein as “carbocycle” or“cycloalkyl”), that has a single point of attachment to the rest of themolecule wherein any individual ring in said bicyclic ring system has3-7 members. For example, suitable aliphatic groups include, but are notlimited to, linear or branched or alkyl, alkenyl, alkynyl groups andhybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

The terms “alkyl”, “alkoxy”, “hydroxyalkyl”, “alkoxyalkyl”, and“alkoxycarbonyl”, used alone or as part of a larger moiety include bothstraight and branched chains containing one to twelve carbon atoms. Theterms “alkenyl” and “alkynyl” used alone or as part of a larger moietyshall include both straight and branched chains containing two to twelvecarbon atoms.

The term “heteroatom” means nitrogen, oxygen, or sulfur and includes anyoxidized form of nitrogen and sulfur, and the quaternized form of anybasic nitrogen. Also the term “nitrogen” includes a substitutablenitrogen of a heterocyclic ring. As an example, in a saturated orpartially unsaturated ring having 0-3 heteroatoms selected from oxygen,sulfur or nitrogen, the nitrogen may be N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl).

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic, bicyclicand tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic and whereineach ring in the system contains 3 to 7 ring members. The term “aryl”may be used interchangeably with the term “aryl ring”. The term “aryl”also refers to heteroaryl ring systems as defined hereinbelow.

The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as used hereinmeans non-aromatic, monocyclic, bicyclic or tricyclic ring systemshaving five to fourteen ring members in which one or more ring membersis a heteroatom, wherein each ring in the system contains 3 to 7 ringmembers.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclicand tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) orheteroaryl (including heteroaralkyl and heteroarylalkoxy and the like)group may contain one or more substituents. Suitable substituents on theunsaturated carbon atom of an aryl, heteroaryl, aralkyl, orheteroaralkyl group are selected from halogen, —R°, —OR°, —SR°,1,2-methylene-dioxy, 1,2-ethylenedioxy, phenyl (Ph) optionallysubstituted with R°, —O(Ph) optionally substituted with R°, —CH₂(Ph)optionally substituted with R°, —CH₂CH₂(Ph),optionally substituted withR°, —NO₂, —CN, —N(RO)₂, —NR°C(O)R°, —NR°C(O)N(R°)₂, —NR°CO₂R°,—NR°NR°C(O)R°, —NR°NR°C(O)N(R°)₂, —NR°NR°CO₂R°, —C(O)C(O)R°,—C(O)CH₂C(O)R°, —CO₂R°, —C(O)R°, —C(O)N(R°)₂, —OC(O)N(R°)₂, —S(O)₂R°,—SO₂N(R°)₂, —S(O)R°, —NR°SO₂N(R°)₂, —NR°SO₂R°, —C(═S)N(R°)₂,—C(═NH)—N(R°)₂, or —(CH₂)_(y)NHC(O)R°, wherein each R° is independentlyselected from hydrogen, optionally substituted C₁₋₆ aliphatic, anunsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl,—O(Ph), or —CH₂(Ph). Optional substituents on the aliphatic group of R°are selected from NH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄ aliphatic)₂, halogen,C₁₋₄ aliphatic, OH, O(C₁₋₄ aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic), O(halo C₁₋₄ aliphatic), or halo C₁₋₄ aliphatic.

An aliphatic group or a non-aromatic heterocyclic ring may contain oneor more substituents. Suitable substituents on the saturated carbon ofan aliphatic group or of a non-aromatic heterocyclic ring are selectedfrom those listed above for the unsaturated carbon of an aryl orheteroaryl group and the following: ═O, ═S, ═NNHR*, ═NN(R*)₂,═NNHC(O)R*, ═NNHCO₂(alkyl), ═NNHSO₂(alkyl), or ═NR*, where each R* isindependently selected from hydrogen or an optionally substituted C₁₋₆aliphatic. Optional substituents on the aliphatic group of R* areselected from NH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄ aliphatic)₂, halogen, C₁₋₄aliphatic, OH, O(C₁₋₄ aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄ aliphatic),O(halo C₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic).

Optional substituents on the nitrogen of a non-aromatic heterocyclicring are selected from —R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺,—C(O)CH₂C(O)R⁺, —SO₂R⁺, —SO₂N(R⁻)₂, —C(═S)N(R⁺)₂, —C(═NH)—N(R⁺)₂, or—NR⁺SO₂R⁺; wherein R⁺ is hydrogen, an optionally substituted C₁₋₆aliphatic, optionally substituted phenyl, optionally substituted —O(Ph),optionally substituted —CH₂(Ph), optionally substituted —CH₂CH₂(Ph), oran unsubstituted 5-6 membered heteroaryl or heterocyclic ring. Optionalsubstituents on the aliphatic group or the phenyl ring of R⁺ areselected from NH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄ aliphatic)₂, halogen, C₁₋₄aliphatic, OH, O(C₁₋₄ aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄ aliphatic),O(halo C₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic).

The term “alkylidene chain” refers to a straight or branched carbonchain that may be fully saturated or have one or more units ofunsaturation and has two points of attachment to the rest of themolecule.

A combination of substituents or variables is permissible only if such acombination results in a stable or chemically feasible compound. Astable compound or chemically feasible compound is one that is notsubstantially altered when kept at a temperature of 40° C. or less, inthe absence of moisture or other chemically reactive conditions, for atleast a week.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.Unless otherwise stated, structures depicted herein are also meant toinclude compounds that differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by a ¹³C— or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools or probes in biological assays.

According to one embodiment, the present invention relates to a compoundof formula I:

or a pharmaceutically acceptable derivative thereof, wherein R¹ and Ar¹are as defined above, provided that: when Ar¹ is phenyl with two R²substituents, then the two

-   -   R² are not simultaneously OR in the meta and para positions of        Ar¹.

According to another embodiment, the present invention relates to acompound of formula I:

or a pharmaceutically acceptable derivative thereof, wherein R¹ and Ar¹are as defined above, provided that: R¹ is other than CN.

Preferred Ar¹ groups of formula I are optionally substituted ringsselected from:

-   -   (a) a phenyl, indanyl, or naphthyl ring;    -   (b) a 5-6 membered heterocyclic ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, or sulfur; or    -   (c) a 5-6 membered monocyclic or 9-10 membered bicyclic        heteroaryl ring having 1-2 heteroatoms independently selected        from oxygen, nitrogen, or sulfur.

More preferred Arl groups of formula I are rings selected from:

-   -   (a) a phenyl, indanyl, or naphthyl ring;    -   (b) a 5-6 membered heterocyclic ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, or sulfur; or    -   (c) a 5-6 membered monocyclic heteroaryl ring having 1-2        nitrogens, wherein:        -   Ar¹ is substituted by one to four substituents selected from            the group consisting of:            -   (a) one group selected from QR, Ar², or QAr²; and            -   (b) up to four R² groups.

Most preferred Ar¹ rings are selected from substituted phenyl, indanyl,naphthyl, pyrimidinyl, or pyridyl. Preferred R² substituents on Ar¹ arehalogen, CN, CO₂R, R, NO₂, OR, haloalkyl, SO₂N(R)₂, or N(R)₂. Morepreferred R² substituents on Ar⁻ are fluoro, iodo, chloro, bromo,CO₂CH₃, methyl, ethyl, t-butyl, NH₂, NHMe, N(Me)₂, OH, OCH₃, OCH₂CH₃,CF₃, SO₂NH₂, or SO₂NHMe. Other preferred compounds include those wheretwo R² are taken together to form a methylenedioxy or an ethylenedioxysubstituent.

Preferred QR or QAr² substituents on Arl of formula I are those whereinQ is a C₁₋₄ alkylidene chain wherein one or two methylene units of Q areoptionally replaced by O, NR, NRCO, NRCO₂, NRSO₂, or CONR, wherein eachR is hydrogen or an optionally substituted C₁₋₄ aliphatic group andwherein Ar² is a 3-6 membered carbocyclic ring or an optionallysubstituted phenyl, 5-6 membered heterocyclic, or heteroaryl ring havingone to two heteroatoms independently selected from nitrogen, oxygen, orsulfur.

The Ar² group of the QA² moiety of formula I is optionally substitutedwith R, OR, N(R)₂, SO₂R, halogen, NO₂, CN, SR, SO₂N(R)₂, CO₂R, C(O)R, oroxo. More preferred QAr² groups of formula I are selected fromO(CH₂)₃pyrrolidin-1-yl, O(CH₂)₂morpholin-4-yl,O(CH₂)₃(4-hydroxyethylpiperazin-1-yl), O(CH₂)₃piperazin-1-yl,O(CH₂)₃(4-hydroxymethylpiperidin-1-yl),O(CH₂)₃(4-hydroxypiperidin-1-yl), NHCOCH₂pyridin-2-yl,NHCOCH₂(2-aminothiazol-4-yl), NHCOCH₂cyclopropyl,NHCO(CH₂)₂(piperazin-2,5-dione-3-yl), NHCOpyrrolidin-1-yl,NHComorpholin-4-yl, NHCO₂CH₂tetrahydrofuran-2-yl,NHCO₂tetrahydrofuran-2-yl, NHCO₂tetrahydropyran-4-yl,NHCO₂CH₂tetrahydropyran-2-yl, Ophenyl, OCH₂(cyclohexyl), OCH₂phenyl,OCH₂(3-CN-phenyl), OCH₂(2-NO₂-phenyl), OCH₂(3-NH₂-phenyl),OCH₂(4-CO₂R-phenyl), OCH₂-pyridyl, OCH₂(mono-, di-, or tri-halogenatedphenyl), OCH₂(C₁-C₆ aliphatic substituted phenyl), OCH₂CH₂-pyrrolyl,OCH₂-pyrrolyl, and OCH₂(phenyl substituted with one or two R²)

Preferred Ar² substituents on Ar¹ of formula I are optionallysubstituted rings selected from:

-   -   (a) a phenyl, indanyl, or naphthyl ring;    -   (b) a 5-6 membered heterocyclic ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, or sulfur; or    -   (c) a 5-6 membered monocyclic or 9-10 membered bicyclic        heteroaryl ring having 1-2 heteroatoms independently selected        from oxygen, nitrogen, or sulfur, wherein:        -   Ar² is optionally substituted with 1-2 R² groups.

More preferred Ar² substituents on Ar¹ of formula I are optionallysubstituted rings selected from phenyl, pyridyl, indolyl, naphthyl, orbenzo[1,3]dioxolyl.

Preferred R² groups, when present, on the Ar² substituent on Ar¹ offormula I are selected from R, halogen, NO₂, CN, OR, SR, N(R)₂, C(O)R,SO₂N(R)₂, or SO₂R. More preferred R² groups, when present, on the Ar²substituent on Ar¹ of formula I are selected from methyl, ethyl,t-butyl, fluoro, chloro, bromo, CF₃, OMe, OEt, CN, SO₂Me, SO₂NH₂, NH₂,NHMe, N(Me)₂, SMe, SEt, OH, C(O)Me, NO₂, or CH₂OH.

One embodiment of this invention relates to a compound of formula Ia:

or a pharmaceutically acceptable derivative thereof, wherein Ar¹ is asdefined above.

Preferred Ar¹ groups of formula Ia are those described above for formulaI.

Another embodiment of this invention relates to a compound of formulaII:

or a pharmaceutically acceptable derivative thereof, wherein R² is asdefined above.

Preferred R² groups of formula II are those defined above for formula Iand include those where two R² are taken together to form amethylenedioxy or an ethylenedioxy substituent.

A preferred embodiment of this invention relates to a compound offormula IIa or IIa′:

or a pharmaceutically acceptable derivative thereof, wherein QR, QAr²and R² are as defined above.

Preferred R² groups of formula IIa or IIa′ are those described above forcompounds of formula I.

Preferred QR and QAr² groups of formula IIa or IIa′ are those describedabove for compounds of formula I.

Another preferred embodiment relates to a compound of formula III:

or a pharmaceutically acceptable derivative thereof, wherein R¹, R², andQAr² are as defined above.

Preferred R² and QAr² groups of formula III are those described abovefor formula I.

Preferred R¹ groups of formula III are selected from hydrogen, N(R)₂,SR, OR, or TR. More preferred R¹ groups are selected from OH, OCH₃,CH₂OH, CH₂OCH₃, CH₂NH₂, or CH₂NHCH₃.

Another preferred embodiment relates to a compound of formula IV:

or a pharmaceutically acceptable derivative thereof, wherein R² and Ar²are as defined above.

Preferred R² and Ar² groups of formula IV are those described above forcompounds of formula I.

Exemplary structures of formula I are set forth in Table 1 below. TABLE1 Compounds of Formula I Cmpd I- Structure  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

— — 33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100 

101 

— — 103 

104 

105 

106 

107 

108 

109 

110 

111 

112 

113 

114 

115 

116 

117 

Exemplary structures of formulae IIa and IIa′ forth in Table 2 below.TABLE 2 Compounds of Formulae IIa and IIa′ IIa-1 IIa-2

IIa-3 IIa-4

IIa-5 IIa-6

IIa-7 IIa-8

IIa-9 IIa-10

IIa-11 IIa-12

IIa-13 IIa-14

IIa-15 IIa-16

IIa-17 IIa-18

IIa-19 IIa-20

IIa-21 IIa-22

IIa-23 IIa-24

IIa-25 IIa-26

IIa-27 IIa-28

IIa-29 IIa-30

IIa-31 IIa-32

IIa-33 IIa-34

IIa-35 IIa-36

IIa-37 IIa-38

IIa-39 IIa-40

IIa-41 IIa-42

IIa-43 IIa-44

IIa-45 IIa-46

IIa-47 IIa-48

IIa-49 IIa-50

The present compounds may be prepared in general by methods known tothose skilled in the art for analogous compounds, as illustrated by thegeneral Scheme I and the synthetic examples shown below.

Scheme I above shows a general synthetic route that may be used used forpreparing compounds of formula I.

In step (a), a solution of 2-acetyl thiazole (1) in THF is treated withdimethylformamide-dimethylacetal and the resulting mixture stirred atroom temperature over night. The reaction mixture is concentrated invacuo and the concentrate triturated with diethyl ether to afford 2.

To prepare intermediate 4 from aniline 3 in step (b), a mixture of 3 andcyanamide in HCl (4N in dioxane) is heated at 120° C. overnight. Aftercooling to room temperature, aqueous work-up affords the desiredguanidine compound 4. One of skill in the art would recognize that awide variety of aryl guanidines may be prepared at step (b) and, thus,be used to prepare compounds of formula I with a wide variety of Ar¹rings.

In step (c), guanidine 4 is combined with enaminone 2 in ethanol in asealed tube. The resulting mixture is heated at reflux overnight thenconcentrated and the crude product purified by column chromatography toafford the desired pyrimidine compound 5. The details of the conditionsused for producing these compounds are set forth in the Examples.

The activity of a compound utilized in this invention as an inhibitor ofGSK3, Aurora2, or Syk protein kinase may be assayed in vitro, in vivo orin a cell line according to methods known in the art and by the methodsset forth in the Examples below. In vitro assays include assays thatdetermine inhibition of either the phosphorylation activity or ATPaseactivity of activated GSK3, Aurora2, or Syk protein kinase. Alternate invitro assays quantitate the ability of the inhibitor to bind to GSK3,Aurora2, or Syk protein kinase. Inhibitor binding may be measured byradiolabelling the inhibitor prior to binding, isolating theinhibitor/GSK3, inhibitor/Aurora2, or inhibitor/Syk complex anddetermining the amount of radiolabel bound. Alternatively, inhibitorbinding may be determined by running a competition experiment where newinhibitors are incubated with GSK3, Aurora2, or Syk protein kinase boundto known radioligands. Detailed conditions for assaying a compoundutilized in this invention as an inhibitor of GSK3, Aurora2, or Sykprotein kinase are set forth in the Examples below.

According to another embodiment, the present invention provides acomposition, or pharmaceutically acceptable composition, comprising acompound of this invention or a pharmaceutically acceptable derivativethereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.The amount of compound in the compositions of this invention is suchthat is effective to detectably inhibit a protein kinase, particularlyGSK3, Aurora2, or Syk protein kinase, in a biological sample or in apatient. Preferably the composition of this invention is formulated foradministration to a patient in need of such composition. Mostpreferably, the composition of this invention is formulated for oraladministration to a patient.

The term “patient”, as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

The term “detectably inhibit”, as used herein means a measurable changein GSK3, Aurora2, or Syk protein kinase activity between a samplecomprising said composition and a GSK3, Aurora2, or Syk protein kinaseand an equivalent sample comprising GSK3, Aurora2, or Syk protein kinasein the absence of said composition.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitorily active metabolite or residue thereof. As used herein,the term “inhibitorily active metabolite or residue thereof” means thata metabolite or residue thereof is also an inhibitor of a GSK3, Aurora2,or Syk protein kinase.

Pharmaceutically acceptable salts of the compounds of this inventioninclude those derived from pharmaceutically acceptable inorganic andorganic acids and bases. Examples of suitable acid salts includeacetate, adipate, alginate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, citrate, camphorate, camphorsulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptanoate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, salicylate, succinate, sulfate, tartrate,thiocyanate, tosylate and undecanoate. Other acids, such as oxalic,while not in themselves pharmaceutically acceptable, may be employed inthe preparation of salts useful as intermediates in obtaining thecompounds of the invention and their pharmaceutically acceptable acidaddition salts.

Salts derived from appropriate bases include alkali metal (e.g., sodiumand potassium), alkaline earth metal (e.g., magnesium), ammonium andN⁺(C₁₋₄ alkyl)₄ salts. This invention also envisions the quaternizationof any basic nitrogen-containing groups of the compounds disclosedherein. Water or oil-soluble or dispersible products may be obtained bysuch quaternization.

The compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

The pharmaceutically acceptable compositions of this invention may beorally administered in any orally acceptable dosage form including, butnot limited to, capsules, tablets, aqueous suspensions or solutions. Inthe case of tablets for oral use, carriers commonly used include lactoseand corn starch. Lubricating agents, such as magnesium stearate, arealso typically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

The pharmaceutically acceptable compositions of this invention may alsobe administered topically, especially when the target of treatmentincludes areas or organs readily accessible by topical application,including diseases of the eye, the skin, or the lower intestinal tract.Suitable topical formulations are readily prepared for each of theseareas or organs.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutically acceptable compositionsmay be formulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutically acceptable compositions canbe formulated in a suitable lotion or cream containing the activecomponents suspended or dissolved in one or more pharmaceuticallyacceptable carriers. Suitable carriers include, but are not limited to,mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax,cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutically acceptable compositions may beformulated as micronized suspensions in isotonic, pH adjusted sterilesaline, or, preferably, as solutions in isotonic, pH adjusted sterilesaline, either with or without a preservative such as benzylalkoniumchloride. Alternatively, for ophthalmic uses, the pharmaceuticallyacceptable compositions may be formulated in an ointment such aspetrolatum.

The pharmaceutically acceptable compositions of this invention may alsobe administered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, the pharmaceutically acceptable compositions of thisinvention are formulated for oral administration.

The amount of the compounds of the present invention that may becombined with the carrier materials to produce a composition in a singledosage form will vary depending upon the host treated, the particularmode of administration. Preferably, the compositions should beformulated so that a dosage of between 0.01-100 mg/kg body weight/day ofthe inhibitor can be administered to a patient receiving thesecompositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Depending upon the particular condition, or disease, to be treated orprevented, additional therapeutic agents, which are normallyadministered to treat or prevent that condition, may also be present inthe compositions of this invention. As used herein, additionaltherapeutic agents that are normally administered to treat or prevent aparticular disease, or condition, are known as “appropriate for thedisease, or condition, being treated”.

For example, in the treatment of diabetes other anti-diabetic agents maybe combined with the compounds of this invention to treat diabetes.These agents include, without limitation, insulin in injectable orinhalation form, insulin analogues, glitazones, sulfonyl ureas, alphaglucosidase inhibitors, biguanides, and insulin sensitizers.

Other examples of agents the inhibitors of this invention may also becombined with include, without limitation: chemotherapeutic agents suchas Gleevec™, adriamycin, dexamethasone, vincristine, cyclophosphamide,fluorouracil, topotecan, taxol, interferons, and platinum derivatives;treatments for Alzheimer's Disease such as Aricept® and Excelon®;treatments for Parkinson's Disease such as L-DOPA/carbidopa, entacapone,ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, andamantadine; agents for treating Multiple Sclerosis (MS) such as betainterferon (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone;treatments for asthma such as albuterol and Singulair®; agents fortreating schizophrenia such as zyprexa, risperdal, seroquel, andhaloperidol; anti-inflammatory agents such as corticosteroids, TNFblockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine;immunomodulatory and immunosuppressive agents such as cyclosporin,tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophophamide, azathioprine, and sulfasalazine;neurotrophic factors such as acetylcholinesterase inhibitors, MAOinhibitors, interferons, anti-convulsants, ion channel blockers,riluzole, and anti-Parkinsonian agents; agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins; agents for treatingliver disease such as corticosteroids, cholestyramine, interferons, andanti-viral agents; agents for treating blood disorders such ascorticosteroids, anti-leukemic agents, and growth factors; and agentsfor treating immunodeficiency disorders such as gamma globulin.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

According to another embodiment, the invention relates to a method ofinhibiting GSK3 protein kinase activity in a biological samplecomprising the step of contacting said biological sample with a compoundof this invention, or a composition comprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting Aurora2 protein kinase activity in a biological samplecomprising the step of contacting said biological sample with a compoundof this invention, or a composition comprising said compound.

According to another embodiment, the invention relates to a method ofinhibiting Syk protein kinase activity in a biological sample comprisingthe step of contacting said biological sample with a compound of thisinvention, or a composition comprising said compound.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of GSK3, Aurora2, or Syk protein kinase activity in abiological sample is useful for a variety of purposes that are known toone of skill in the art. Examples of such purposes include, but are notlimited to, blood transfusion, organ-transplantation, biologicalspecimen storage, and biological assays.

According to another embodiment, the invention provides a method fortreating or lessening the severity of a GSK3-mediated disease orcondition in a patient comprising the step of administering to saidpatient a composition according to the present invention.

The term “GSK3-mediated disease” or “GSK3-mediated condition”, as usedherein, means any disease or other deleterious condition in which GSK3protein kinase is known to play a role. Such conditions include, withoutlimitation, diabetes, neurodegenerative disorders, Alzheimer's disease,Huntington's, Parkinson's, AIDS associated dementia, amyotrophic lateralsclerosis (AML), multiple sclerosis (MS), schizophrenia, stroke,cardiomycete hypertrophy, and baldness.

According to another embodiment, the invention provides a method fortreating or lessening the severity of an Aurora2-mediated disease orcondition in a patient comprising the step of administering to saidpatient a composition according to the present invention.

The term “Aurora2-mediated disease” or “Aurora2-mediated condition”, asused herein, means any disease or other deleterious condition in whichAurora2 protein kinase is known to play a role. Such conditions include,without limitation, cancers such as colon and breast cancer.

According to another embodiment, the invention provides a method fortreating or lessening the severity of a Syk-mediated disease orcondition in a patient comprising the step of administering to saidpatient a composition according to the present invention.

The term “Syk-mediated disease” or “Syk-mediated condition”, as usedherein, means any disease or other deleterious condition in which Sykprotein kinase is known to play a role. Such conditions include, withoutlimitation, allergic disorders, especially asthma.

In an alternate embodiment, the methods of this invention that utilizecompositions that do not contain an additional therapeutic agent,comprise the additional step of separately administering to said patientan additional therapeutic agent. When these additional therapeuticagents are administered separately they may be administered to thepatient prior to, sequentially with or following administration of thecompositions of this invention.

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

EXAMPLES Example 1

3-Dimethylamino-1-thiazol-2-yl-propenone (2): To a solution of2-acetylthiazole (500 mg, 3.93 mmol) in 2 mL of THF was addeddimethylformamide-dimethylacetal (1.6 ml, 7.86 mmol) and the resultingsolution was stirred at room temperature overnight. The reaction mixturewas evaporated and the residue triturated with ethyl acetate and theproduct isolated by filtration. The filtered solid was washed withdiethyl ether and dried to afford 2 (400 mg) as a yellow solid.

Example 2

N-(3-Benzyloxy-phenyl)-guanidine (4): 3-benzyloxy aniline (1 g, 5 mmol)and cyanamide (420 mg, 10 mmol) were dissolved in 4 mL of 4N HCl indioxane and heated to 120° C. overnight. The reaction mixture was cooledto room temperature, quenched with water, and extracted with diethylether. The aqueous layer was made basic with 2N NaOH and extractedthrice with dichloromethane. The organic extracts were combined andwashed with brine, dried over MgSO₄, and concentrated to afford 4 (450mg) as a light brown solid.

Example 3

(3-Benzyloxy-phenyl)-(4-thiazol-2-yl-pyrimidin-2-yl)-amine (I-7): Asolution of 3-benzyloxy guanidine 4 (50 mg, 0.20 mmol) and enaminone 2(50 mg, 0.27 mmol) in ethanol (3 mL) was heated at reflux in a sealedtube overnight. The reaction mixture was concentrated and the residuepurified by column chromatography to afford compound I-7 (20 mg). M+1(obs) 347.1. R_(t)=4.28 minutes.

Example 4

We have prepared other compounds of formula I by methods substantiallysimilar to those described in the above Examples 1-3 and thoseillustrated in Scheme I. The characterization data for these compoundsis summarized in Table 3 below and includes LC/MS (M+1 observed), HPLC,and ¹HNMR data.

The term “R_(t)(min)” refers to the retention time, in minutes,associated with the compound using the following HPLC method. The R_(t)was determined using a Waters ODS-AQ (2×50 mm) column at ambienttemperature with a gradient of 10→90% CH₃CN in water over 5 minutes andwith the absorbance detected as an average of 190-380 nM @ 4 nMincrements.

The term “Y” designates that ¹HNMR data was obtained and found to beconsistant with the assigned structure. Compound numbers correspond tothe compound numbers listed in Table 1. TABLE 3 Characterization Datafor Selected Compounds of Formula I Compound No M + 1 (obs) R_(t) (min)¹H NMR I-16 300.0 3.15 — I-19 273.0 3.18 — I-22 289.0 3.47 — I-28 290.02.76 — I-31 381.0 3.66 — I-34 334.8 3.54 — I-37 323.0 3.56 — I-40 300.03.19 — I-43 273.0 3.1 — I-46 289.0 3.19 — I-49 291.0 3.33 — I-52 305.03.62 — I-55 334.0 2.16 — I-58 309.0 3.60 — I-61 322.9 2.99 — I-64 291.02.67 — I-67 269.0 3.28 — I-73 283.0 3.53 — I-10 361.1 3.76 — I-13 347.03.82 — I-4 347.1 4.14 — I-7 361.1 4.28 — I-25 285.0 2.98 — I-76 367.24.53 — I-79 386.1 3.58 — I-82 419.1 3.80 — I-85 397.1 3.94 — I-88 395.14.11 — I-100 379.1 3.85 — I-103 397.1 3.98 — I-106 429.1 4.13 — I-109379.1 3.84 — I-112 429.0 4.40 — I-115 375.2 3.96 — I-2 429.0 4.38 — I-5439.1 3.24 — I-8 362.1 2.21 — I-11 — — Y I-14 376.2 2.56 — I-17 405.13.72 — I-20 362.1 2.54 — I-23 362.1 2.55 — I-29 364.2 3.52 — I-35 406.13.8 Y I-38 376.1 3.13 Y I-41 379.2 3.84 — I-44 391.1 3.84 — I-47 429.14.12 — I-91 429.1 4.12 — I-94 397.1 3.75 —

Example 5 GSK-3 Inhibition Assay

Compounds were screened for their ability to inhibit GSK3-β (AA 1-420)activity using a standard coupled enzyme system (Fox et al. (1998)Protein Sci. 7, 2249). Reactions were carried out in a solutioncontaining 100 mM HEPES (pH 7.5), 10 mM MgCl₂, 25 mM NaCl, 300 μM NADH,1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay were10 μM ATP (Sigma Chemicals, St Louis, Mo.) and 300 μM peptide(HSSPHQS(PO₃H₂)EDEEE, American Peptide, Sunnyvale, Calif.). Reactionswere carried out at 30° C. and 60 nM GSK-3β. Final concentrations of thecomponents of the coupled enzyme system were 2.5 mM phosphoenolpyruvate,300 μM NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactatedehydrogenase.

An assay stock buffer solution was prepared containing all of thereagents listed above with the exception of ATP and the test compound ofinterest. 59 μl of the test reaction was placed in a 96 well ½-diameterplate (Corning, Corning, NY) then treated with 1 μl of a 2 mM DMSO stockcontaining the test compound (final compound concentration 30 μM). Theplate was incubated for ˜10 minutes at 30° C. then the reactioninitiated by addition of 7 μl of ATP (final concentration 10 μM). Ratesof reaction were obtained using a Molecular Devices Spectramax platereader (Sunnyvale, CA) over a 5 minute read time at 30° C. Compoundsshowing greater than 50% inhibition versus standard wells containingDMSO, but no compound, were titrated and K_(i) values were determined.

Table 4 shows the results of the activity of selected compounds of thisinvention in the GSK3 inhibition assay. The compound numbers correspondto the compound numbers in Table 1. Compounds having a K_(i) less than0.1 micromolar (μM) are rated “A”, compounds having a K_(i) between 0.1and 1 μM are rated “B” and compounds having a K_(i) greater than 1 μMare rated “C”. TABLE 4 GSK3-β Activity of Selected Compounds No. I-Activity No. I- Activity No. I- Activity 16 C 19 A 22 A 28 A 31 A 34 A37 A 40 A 43 A 46 A 49 A 52 A 55 A 58 A 61 C 64 C 67 B 73 A 10 C 4 A 7 —25 A 76 A 79 A 82 A 85 A 88 A 100 A 103 A 106 A 109 A 112 A 115 A 2 C 5A 8 A 11 A 14 A 17 A 20 A 23 A 29 A 35 A 38 A 41 A 44 A 47 A 91 A 94 A 3A 6 A 9 A 12 A 15 A 18 A 21 C 24 A 27 A 30 A 33 A 36 B 39 A 42 A 45 A 48A 51 B 54 A 57 A 60 A 63 A 66 A 69 A 72 A 75 A 78 A 81 A 84 A 87 A 90 A93 C 96 C 99 A — — 105 A 108 B 111 A 114 C 117 C — — — —

Example 6 Aurora2 Inhibition Assay

Compounds are screened in the following manner for their ability toinhibit Aurora2 using a standard coupled enzyme assay (Fox et al (1998)Protein Sci 7, 2249). To an assay stock buffer solution containing 0.1MHEPES 7.5, 10 mM MgCl₂, 1 mM DTT, 25 mM NaCl, 2.5 mMphosphoenolpyruvate, 300 mM NADH, 30 mg/ml pyruvate kinase, 10 mg/mllactate dehydrogenase, 40 mM ATP, and peptide (LRRASLG, AmericanPeptide, Sunnyvale, Calif.) is added a DMSO solution of a compound ofthe present invention to a final concentration of 30 μM. The resultingmixture is incubated at 30° C. for 10 minutes. The reaction wasinitiated by the addition of 10 μL of Aurora2 stock solution to give afinal concentration of 70 nM in the assay. The rates of reaction areobtained by monitoring absorbance at 340 nm over a 5 minute read time at30° C. using a BioRad Ultramark plate reader (Hercules, Calif.). TheIC₅₀ values are determined from the rate data as a function of inhibitorconcentration.

Table 5 shows the results of the activity of selected compounds of thisinvention in the Aurora2 inhibition assay. The compound numberscorrespond to the compound numbers in Table 1. Compounds having an IC₅₀less than 0.5 micromolar (μM) are rated “A”, compounds having an IC₅₀between 0.5 and 2 μM are rated “B” and compounds having an IC₅₀ greaterthan 2 μM are rated “C”. TABLE 5 Aurora2 Activity of Selected CompoundsNo. I- Activity No. I- Activity No. I- Activity 2 C 4 B 5 C 7 C 8 A 10 C11 A 13 C 14 B 16 A 17 A 19 B 20 A 22 A 23 A 25 B 26 A 28 C 29 A 31 A —— 34 A 35 C 37 B 38 A 40 C 41 C 43 C 46 C 49 B 50 B 52 C 55 A 56 B 58 C59 C 61 C 62 B 64 C 67 A 70 B 73 A 76 C 79 C 82 C 85 C 88 B 91 C 94 A 97C 100 C 103 C 106 C 109 C 112 C 114 B — —

Example 7 Syk Inhibition Assay

Compounds were screened for their ability to inhibit Syk using astandard coupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249).Reactions were carried out in 100 mM HEPES pH 7.5, 10 mM MgCl2, 25 mMNaCl, 1 mM DTT and 1.5% DMSO. Final substrate concentrations in theassay were 200 μM ATP (Sigma chemical Co.) and 4 μM poly Gly-Tyr peptide(Sigma Chemical Co.). Assays were carried out at 30° C. and 200 nM Syk.Final concentrations of the components of the coupled enzyme system were2.5 mM phosphoenolpyruvate, 300 μM NADH, 30 μg/ml pyruvate kinase and 10μg/ml lactate dehydrogenase.

An assay stock buffer solution was prepared containing all of thereagents listed above, with the exception of Syk, DTT and the testcompound of interest. 56 μl of the test reaction was placed in a 96 wellplate followed by the addition of 1 μl of 2 mM DMSO stock containing thetest compound (final compound concentration 30 μM). The plate waspre-incubated for ˜10 minutes at 30° C. and the reaction initiated bythe addition of 10 μl of enzyme (final concentration 25 nM). Rates ofreaction were obtained using a BioRad Ultramark plate reader (Hercules,Calif.) over a 5 minute read time at 30° C. Compounds showing >50 %inhibition versus standard wells containing DMSO, but no compound, weretitrated and IC50's determined using a similar protocol.

Table 6 shows the results of the activity of selected compounds of thisinvention in the Syk inhibition assay. The compound numbers correspondto the compound numbers in Table 1. Compounds having an IC₅₀ less than0.5 micromolar (μM) are rated “A”, compounds having an IC₅₀ between 0.5and 2 μM are rated “B” and compounds having an IC₅₀ greater than 2 μMare rated “C”. TABLE 6 Syk Activity of Selected Compounds No. I-Activity No. I- Activity No. I- Activity 2 C 4 B 5 A 7 A 8 C 11 A 14 B16 B 17 A 19 B 22 A 23 A 25 A 29 A 31 A 34 A 35 C 37 A 38 A 43 C 44 A 46C 47 C 49 C 50 A 52 C 53 B 55 A 56 B 58 C 59 C 61 C 62 A 64 C 67 A 73 A76 C 82 C 88 C 91 C 94 A 106 C 109 C 112 C 115 C

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

1. A compound of formula I:

or a pharmaceutically acceptable derivative thereof, wherein: R¹ isselected from R, halogen, CN, NO₂, or TR; T is an optionally substitutedC₁-C₄ alkylidene chain wherein up to two methylene units of T areoptionally and independently replaced by O, N(R), C(O), S, SO, or SO₂;each R is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, wherein: two R bound to the samenitrogen atom are optionally taken together with the nitrogen to form a3-7 membered saturated, partially unsaturated, or fully unsaturated ringhaving 0-2 heteroatoms, in addition to the nitrogen bound thereto,independently selected from nitrogen, oxygen, or sulfur; Ar¹ is anoptionally substituted ring selected from: (a) a 3-8 membered monocyclicsaturated or partially unsaturated ring; or 8-10 membered bicyclicsaturated, partially unsaturated, or aryl ring; (b) a 3-7 memberedheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; or (c) a 5-6 membered monocyclic or 8-10membered bicyclic heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein: Ar¹ is optionallysubstituted by one to four substituents selected from the groupconsisting of: (a) one group selected from QR. Ar², or QAr²; and (b) upto four R² groups; each Q is independently selected from a valence bondor an optionally substituted C₁₋₆ alkylidene chain, wherein: one or twonon-adjacent methylene units of Q are optionally and independentlyreplaced by —O—, —S—, —NR—, —C(O)—, —CO₂—, —C(O)NR—, —OC(O)NR—,—C(O)C(O)—, —NRC(O)—, NRCO₂—, —NRC(O)NR—, —S(O)—, —SO₂—, —NRSO₂—,—SO₂NR—, or —NRSO₂NR—; each Ar² is an optionally substituted ringindependently selected from:: (a) a 3-8 membered monocyclic or 8-10membered bicyclic saturated, partially unsaturated, or aryl ring; (b) a3-7 membered heterocyclic ring having 1-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; or (c) a 5-6 memberedmonocyclic or 8-10 membered bicyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein: Ar² is optionally substituted by one to four R² groups; andeach R² is independently selected from R, halogen, NO₂, CN, OR, SR,N(R)₂, NRCOR, NRCON(R)₂, NRCO₂R, C(O)R, CO₂R, CON(R)₂, OC(O)N(R)₂, SOR,SO₂R, SO₂N(R)₂, NRSO₂R, NRSO₂N(R)₂, C(O)C(O)R, or C(O)CH₂C(O)R; wherein:two R² on adjacent positions on Ar¹ or Ar² are optionally taken togetherto form a saturated, partially unsaturated, or fully unsaturated 4-6membered ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.
 2. The compound according to claim 1,wherein Ar¹ is a ring selected from: (a) an indanyl or naphthyl ring;(b) a 5-6 membered heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; or (c) a 5-6membered monocyclic heteroaryl ring having 1-2 nitrogens, wherein: Ar¹is substituted by one to four substituents selected from the groupconsisting of: (a) one group selected from QR, Ar², or QAr²; and (b) upto four R² groups.
 3. The compound according to claim 2, wherein: Ar¹ isselected from an indanyl, naphthyl, pyrimidinyl, or pyridyl ring.
 4. Thecompound according to either of claims 2 or 3, wherein: Ar¹ issubstituted by one to four substituents selected from the groupconsisting of: (a) one group selected from QR or QAr²; and (b) up tofour R² groups; wherein: each R² is independently selected from halogen,CN, CO₂R, R, NO₂, OR, haloalkyl, SO₂N(R)₂, or N(R)₂; each Q isindependently selected from a C₁₋₄ alkylidene chain wherein one or twomethylene units of Q are optionally replaced by O, NH, NHCO, NHCO₂,NHSO₂, or CONH; and Ar² is is a 3-6 membered carbocyclic ring or anoptionally substituted phenyl or 5-6 membered heterocyclic or heteroarylring having one to two heteroatoms independently selected from nitrogen,oxygen, or sulfur.
 5. The compound according to either of claims 2 or 3,wherein: Ar¹ is substituted by Ar² and optionally substituted with 1-2R² substituents, wherein: each Ar² is an optionally substituted ringindependently selected from:: (a) a phenyl, indanyl, or naphthyl ring;(b) a 5-6 membered heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; or (c) a 5-6membered monocyclic or 9-10 membered bicyclic heteroaryl ring having 1-2heteroatoms independently selected from oxygen, nitrogen, or sulfur,wherein: Ar² is optionally substituted with 1-2 R² groups; and each R²is independently selected from R, halogen, NO₂, CN, OR, SR, N(R)₂,C(O)R, SO₂N(R)₂, or SO₂R. 6-7. (canceled)
 8. A composition comprising acompound according to claim 1, in an amount to detectably inhibit GSK3,Aurora2, or Syk protein kinase activity, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.
 9. The composition accordingto claim 8, additionally comprising an additional therapeutic agentselected from an anti-diabetic agent, a chemotherapeutic oranti-proliferative agent, a treatment for Alzheimer's Disease, atreatment for Parkinson's Disease, an agent for treating MultipleSclerosis (MS), a treatment for asthma, an agent for treatingschizophrenia, an anti-inflammatory agent, an immunomodulatory orimmunosuppressive agent, a neurotrophic factor, an agent for treatingcardiovascular disease, an agent for treating liver disease, an agentfor treating a blood disorder, or an agent for treating animmunodeficiency disorder.
 10. A method of inhibiting GSK3, Aurora2, orSyk kinase activity in a biological sample, comprising the step ofcontacting said biological sample with: a) a composition according toclaim 8; or b) a compound of formula I:

or a pharmaceutically acceptable derivative thereof, wherein: R¹ isselected from R, halogen, CN, NO₂, or TR; T is an optionally substitutedC₁-C₄ alkylidene chain wherein up to two methylene units of T areoptionally and independently replaced by O, N(R), C(O), S, SO, or SO₂;each R is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, wherein: two R bound to the samenitrogen atom are optionally taken together with the nitrogen to form a3-7 membered saturated, partially unsaturated, or fully unsaturated ringhaving 0-2 heteroatoms, in addition to the nitrogen bound thereto,independently selected from nitrogen, oxygen, or sulfur; Ar¹ is anoptionally substituted ring selected from: (a) a 3-8 membered monocyclicsaturated or partially unsaturated ring; or 8-10 membered bicyclicsaturated, partially unsaturated, or aryl ring; (b) a 3-7 memberedheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; or (c) a 5-6 membered monocyclic or 8-10membered bicyclic heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein: Ar¹ is optionallysubstituted by one to four substituents selected from: (a) one groupselected from QR, Ar², or QAr²; and (b) up to four R² groups; each Q isindependently selected from a valence bond or an optionally substitutedC₁₋₆ alkylidene chain, wherein: one or two non-adjacent methylene unitsof Q are optionally and independently replaced by —O—, —S—, —NR—,—C(O)—, —CO₂—, —C(O)NR—, —OC(O)NR—, —C(O)C(O)—, —NRC(O)—, NRCO₂—,—NRC(O)NR—, —S(O)—, —SO₂—, —NRSO₂—, —SO₂NR—, or —NRSO₂NR—; each Ar² isan optionally substituted ring independently selected from:: (a) a 3-8membered monocyclic or 8-10 membered bicyclic saturated, partiallyunsaturated, or aryl ring; (b) a 3-7 membered heterocyclic ring having1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;or (c) a 5-6 membered monocyclic or 8-10 membered bicyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, wherein: Ar² is optionally substituted by one to fourR² groups; and each R² is independently selected from R, halogen, NO₂,CN, OR, SR, N(R)₂, NRCOR, NRCON(R)₂, NRCO₂R, C(O)R, CO₂R, CON(R)₂,OC(O)N(R)₂, SOR, SO₂R, SO₂N(R)₂, NRSO₂R, NRSO₂N(R)₂, C(O)C(O)R, orC(O)CH₂C(O)R; wherein: two R² on adjacent positions on Ar¹ or Ar² areoptionally taken together to form a saturated, partially unsaturated, orfully unsaturated 4-6 membered ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.
 11. A method of treating orlessening the severity of a GSK3-, Aurora2-, or Syk-mediated disease orcondition in a patient, comprising the step of administering to saidpatient: a) a composition according to claim 8; or b) a compound offormula I:

or a pharmaceutically acceptable derivative thereof, wherein: R¹ isselected from R, halogen, CN, NO₂, or TR; T is an optionally substitutedC₁-C₄ alkylidene chain wherein up to two methylene units of T areoptionally and independently replaced by O, N(R), C(O), S, SO, or SO₂;each R is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, wherein: two R bound to the samenitrogen atom are optionally taken together with the nitrogen to form a3-7 membered saturated, partially unsaturated, or fully unsaturated ringhaving 0-2 heteroatoms, in addition to the nitrogen bound thereto,independently selected from nitrogen, oxygen, or sulfur; Ar¹ is anoptionally substituted ring selected from: (a) a 3-8 membered monocyclicsaturated or partially unsaturated ring; or 8-10 membered bicyclicsaturated, partially unsaturated, or aryl ring; (b) a 3-7 memberedheterocyclic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; or (c) a 5-6 membered monocyclic or 8-10membered bicyclic heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein: Ar¹ is optionallysubstituted by one to four substituents selected from: (a) one groupselected from QR, Ar², or QAr²; and (b) up to four R² groups; each Q isindependently selected from a valence bond or an optionally substitutedC₁₋₆ alkylidene chain, wherein: one or two non-adjacent methylene unitsof Q are optionally and independently replaced by —O—, —S—, —NR—,—C(O)—, —CO₂—, —C(O)NR—, —OC(O)NR—, —C(O)C(O)—, —NRC(O)—, NRCO₂—,—NRC(O)NR—, —S(O)—, —SO₂—, —NRSO₂—, —SO₂NR—, or —NRSO₂NR—; each Ar² isan optionally substituted ring independently selected from:: (a) a 3-8membered monocyclic or 8-10 membered bicyclic saturated, partiallyunsaturated, or aryl ring; (b) a 3-7 membered heterocyclic ring having1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;or (c) a 5-6 membered monocyclic or 8-10 membered bicyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, wherein: Ar² is optionally substituted by one to fourR² groups; and each R² is independently selected from R, halogen, NO₂,CN, OR, SR, N(R)₂, NRCOR, NRCON(R)₂, NRCO₂R, C(O)R, CO₂R, CON(R)₂,OC(O)N(R)₂, SOR, SO₂R, SO₂N(R)₂, NRSO₂R, NRSO₂N(R)₂, C(O)C(O)R, orC(O)CH₂C(O)R; wherein: two R2 on adjacent positions on Ar¹ or Ar² areoptionally taken together to form a saturated, partially unsaturated, orfully unsaturated 4-6 membered ring having 0-3 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.
 12. The method according toclaim 11, wherein said GSK3-mediated disease is selected from diabetes,a neurodegenerative disorder, a CNS disorder, Alzheimer's disease,Huntington's, Parkinson's, AIDS associated dementia, amyotrophic lateralsclerosis (AML), multiple sclerosis (MS), stroke, schizophrenia,cardiomycete hypertrophy, a manic depressive disorder, or baldness. 13.The method according to claim 11, wherein said Aurora2-mediated diseaseis selected from cancer.
 14. The method according to claim 11, whereinsaid Syk-mediated disease is selected from an allergic disorder.
 15. Themethod according to claim 11, comprising the additional step ofadministering to said patient an additional therapeutic agent selectedfrom an anti-diabetic agent, a chemotherapeutic or anti-proliferaticagent, a treatment for Alzheimer's Disease, a treatment for Parkinson'sDisease, an agent for treating Multiple Sclerosis (MS), a treatment forasthma, an agent for treating schizophrenia, an anti-inflammatory agent,an immunomodulatory or immunosuppressive agent, a neurotrophic factor,an agent for treating cardiovascular disease, an agent for treatingliver disease, an agent for treating a blood disorder, or an agent fortreating an immunodeficiency disorder, wherein: said additionaltherapeutic agent is appropriate for the disease being treated; and saidadditional therapeutic agent is administered together with saidcomposition as a single dosage form or separately from said compositionas part of a multiple dosage form.